Zika and Microcephaly: Jury Still Out

Link is strong in some cases but more study is needed

In the matter of microcephaly, the case against Zika virus remains unproven.

The evidence against Zika includes the "explosive" expansion of the virus in South and Central America that coincides with an apparent spike in microcephaly in Brazil, along with evidence of viral genetic material in six of the roughly 4,000 reported cases.

There is also evidence of a similar association of Zika virus with Guillain-Barré syndrome, a rare disorder in which the body's immune system attacks the nerves.

But on the other side of the coin:

So far just six cases of microcephaly have been strongly linked to Zika

Zika circulated for decades in Africa without raising fears of microcephaly

Just because two things occur at the same time doesn't mean one caused the other and it's not really known how strong is the association between Zika and other cases of microcephaly

There are other viral suspects

It remains unclear if the apparent spike in microcephaly is real

"The association in some individual cases is strong -- those in which Zika genetic material has been found in amniotic fluid, the placenta, the fetus, or the neonate," commented Amesh Adalja, MD, of the University of Pittsburgh.

But, he told MedPage Today, "it is not known if a causal link exists or if other co-factors (other infections, nutritional variables, etc.) are involved."

Zika is a mosquito-borne flavivirus that in most cases causes asymptomatic infection but, in about 25% of patients, mild illness with fever, joint pain, and occasionally rash.

Last fall, Brazilian researchers reported that an outbreak of Zika had occurred in the spring of 2015 in several states. It was a new phenomenon; the virus, discovered in Africa in 1947, had mostly stayed at home until 2007 when it migrated to Micronesia and then to Polynesia in 2011.

It is well known that several viruses can cause damage to infants, Adalja said. "Viruses such as rubella and (cytomegalovirus) can cause microcephaly by causing the death of essential cells or other mechanisms (such as) changing migration patterns of cells, infecting support cells, (or) altering cellular differentiation," he said.

But, he added, he has so far not seen a description of a mechanism by which Zika might cause the disorder.

Importantly, two other mosquito-borne viruses -- dengue fever and chikungunya -- are also circulating in South and Central America, with symptoms that overlap those of Zika and are usually more severe.

It's possible that those viruses might also cause birth defects, so that pinning the charge to Zika will mean ruling them out, something that hasn't been done yet. Indeed, no other causes have been ruled out -- that's something that will take large prospective studies and several months or more of research.

The discrepancy suggests that in the past Brazil has missed a large fraction of its microcephaly cases but, the investigators noted, the number of reported cases (about 20 per 10,000 births) is large enough to remain worrisome.

On the other hand, they also noted that a special notification protocol for microcephaly might have increased reporting and that in any case the presence or absence of Zika virus in most mothers and infants has not been confirmed in the lab.

The link with Guillain-Barré -- also still an association, not a definitive cause-effect relationship -- "illustrates that some individuals are prone to severe complications with Zika infections," Adalja said. The syndrome "is an autoimmune phenomenon triggered by many different types of infection," he said.

Other Causes of Microcephaly

In general, microcephaly is extremely rare, because the tendency of the fetus in utero is to divert resources to the head to make sure it's the last thing that loses growth potential. But microcephaly disturbs that process, so the brain growth -- and thus, the growth of the head -- is interrupted.

Timmy Ho, MD, of Beth Israel Deaconess Medical Center in Boston, said that another way to think of microcephaly is that the head is too small because the brain is not growing normally.

"The way the skull grows is because the brain grows and the brain pushes on the skull, and because the skull bones are spread, they grow in response to brain growth," said Ho. "Instead of devoting resources to brain growth, that process has been interrupted and the body is growing out of proportion to how big the head is."

The causes of microcephaly are varied, but congenital infection can be one of the most common (as would be the case against Zika is eventually proved). There are several congenital infections that are known for causing birth defects, such as toxoplasmosis, rubella, cytomegalovirus, herpes simplex and syphilis. A number of these viruses can also cause microcephaly when contracted by the mother early in pregnancy.

Henry Lee, MD, of the Stanford University School of Medicine in Palo Alto, Calif., said that, like Zika, the symptoms of certain viruses might seem mild and not something that would need urgent medical attention.

"A lot of times, you may not even know that you actually have an infection," he said. "You might have some mild symptoms of some sort, but it's not anything that you would seek out a doctor for, necessarily."

Other potential causes of microcephaly can be genetic conditions (such as a trisomy), metabolic syndrome, brain injury, or even environmental exposures, such as fetal alcohol syndrome.

Microcephaly can be diagnosed prenatally, perinatally, or postnatally, though only the most severe cases are able to be seen prior to birth on an ultrasound, because the head is not generally measured then. Diagnosis generally occurs when the baby is born, and the head circumference is taken. Babies whose heads are considerably smaller compared with infants of the same age and size are considered at risk for microcephaly.

Jenny Wilson, MD, of Oregon Health and Science University in Portland, said that infants who contract microcephaly via prenatal infection tend to have poorer outcomes.

"They tend to not do as well in terms of their outcomes because their head is small because it was injured by a virus," she said. "When you have a viral infection causing brain injury, it's going to have a significant developmental impact."

Prognosis

Once it is determined that an infant has microcephaly, the pediatrician will generally seek a neurology consult, which may include an image of the head, as well as a full genetic work-up. But infants with moderate to severe microcephaly, such as the kind being seen with Zika virus, will generally face a number of developmental disabilities and challenges.

"A lot of babies with microcephaly end up being pretty limited in their capacity. They have trouble eating, they don't talk, they have trouble sitting up, they don't walk. It can be pretty devastating," said Ho.

Lee said that one of the most difficult things about microcephaly that is not due to any kind of specific condition is being unable to tell parents what their child will be like as they grow up.

"That's one of the difficulties with this – we can't predict what's going to happen. We just kind of follow them and see how they do and hopefully try to help them as they grow," he said.

Both Ho and Lee said that getting a patient's travel history has become increasingly important in order to determine potential exposure to Zika virus. But Wilson estimates about a third of the patients in her neurology clinic have microcephaly, though an increase in patients with severe microcephaly from prenatal infection would be notable.

"If we see some increase in microcephaly cases, we'll have to start considering microcephaly in our workup," she said. "But there's only supportive care, and no treatment. Once brain injury has happened, there's no good way of growing brains back."

More in Neurology

MedPageToday is a trusted and reliable source for clinical and policy coverage that directly affects the lives and practices of health care professionals.

Physicians and other healthcare professionals may also receive Continuing Medical Education (CME) and Continuing Education (CE) credits at no cost for participating in MedPage Today-hosted educational activities.